Preclinical evaluation of the efficacy of anti-human SIRPa antibody for cancer immunotherapy using the MITRG humanized mouse model

Tumor-associated macrophages (TAMs) represent abundantly in the tumor microenvironment (TME) and are thought to be novel targets for cancer immunotherapy. To elucidate the antitumor effects of therapeutics targeting human TAMs in vivo, we have here established a preclinical tumor xenograft model using immunodeficient mice expressing multiple human cytokines (MITRG mice) and examined the anti-tumor effect of anti–human SIRPa antibodies SE12C3, which inhibit the interaction of CD47 on tumor cells and enhance Fc? receptor-mediated phagocytosis of tumor cells by human macrophages. Humanized immune system (HIS)–MITRG mice particularly facilitate human macrophage differentiation following transplantation of human CD34+ hematopoietic stem and progenitor cells. HIS–MITRG mice promoted the growth of both cell line– and patient–derived B cell lymphoma and infiltration of human TAMs into the tumor. Treatment of rituximab with SE12C3 markedly inhibited B–cell lymphoma growth in HIS-MITRG mice. The inhibition of B–cell lymphoma growth depended on human macrophages and was attributable to the promotion of rituximab–mediated lymphoma cell phagocytosis by human macrophages. In addition, the treatment of rituximab with SE12C3 induced reprogramming of human TAMs towards the pro-inflammatory phenotype in the TME. Furthermore, we demonstrated that the treatment of rituximab with SE12C3 significantly inhibited diffuse large B–cell lymphoma patient–derived tumor growth in HIS–MITRG mice. Together, HIS–MITRG mice provide an excellent mouse model for in vivo preclinical evaluation of the anti-tumor effect of therapeutics targeting human TAMs in the TME, such as anti–human SIRPa antibodies. Overall design: Comparative gene expression profiling analysis of RNA-seq data for tumor-infiltrating macrophages in Raji inoculated HIS-MITRG mice after the treatment with control IgG, rituximab, or rituximab+SE12C3.